The therapeutic targeting of peroxisome proliferator-activated receptor gamma (PPARγ) for type 2 diabetes (T2D) remains a double-edged sword: while thiazolidinediones are efficacious, their severe side effects necessitate the discovery of safer modulators. We propose a novel nutrient-centred hypothesis that thiamine (vitamin B1), an essential micronutrient, may act as a natural ligand for PPARγ. To investigate this, we adopted a translational approach. Molecular docking and dynamics simulations established that thiamine forms a stable, high-affinity interaction with the PPARγ ligand-binding domain. Functionally, in 3T3-L1 adipocytes, thiamine induced adipogenesis and PPARγ-response element binding with a potency analogous to rosiglitazone, suggesting direct agonistic activity. Corroborating these mechanistic insights at the clinical level, a new meta-analysis of randomized controlled trials demonstrates that high-dose benfotiamine, a synthetic thiamine derivative, significantly improves neuropathic and vascular outcomes in T2D patients. While the contribution of thiamine’s established antioxidant effects to these clinical benefits cannot be ruled out, the synergy of computational, cellular, and human evidence provides a compelling foundation for our hypothesis. This study suggests that thiamine could act as a PPARγ ligand and serve as a safer treatment option for metabolic disorders, which needs to be tested in vivo.
ABSTRACT Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the mechanism of non-carbapenemase carbapenem resistance is still unclear. In the current study, we investigated the contributions of point mutations in mexR, oprD, and ftsI to carbapenem resistance in P. aeruginosa during in vivo evolution studies with consecutive clinical isolates. Real-time qPCR and Electrophoretic Mobility Shift Assay demonstrated that MexR (Gln55Pro) mutation increased MexAB efflux pump genes expression by altering MexR’s binding capacity, leading to a four- to eight-fold increase in meropenem MIC in the Pae d1 Green ∆mexR and PAO1∆mexR mutants. The OprD (Trp415*) truncation affected porin structure, and the constructed mutant Pae d1 Green oprD Trp415* increased meropenem MIC by 16-fold (from 0.25 to 4 µg/mL). The contribution of ftsI mutation to meropenem resistance was confirmed by clinical linkage analysis and was estimated to cause a two-fold increase in meropenem MIC by comparing the resistant clinical isolate with the Pae d1 Green oprD Trp415*∆mexR double mutant. The study found that the oprD Trp415* allele alone accounts for the imipenem MIC in clinical isolates, while the ∆mexR and ftsI Arg504Cys alleles do not contribute to imipenem resistance. In conclusion, we identified and explored the contributions of mexR, oprD, and ftsI mutations to high level non-carbapenemase carbapenem resistance in P. aeruginosa. These findings highlight the interplay of different mutations in causing non-carbapenemase carbapenem-resistance in P. aeruginosa.IMPORTANCEThe emergence of carbapenem-resistant Pseudomonas aeruginosa (CRPA) poses a significant global health threat, complicating treatment options for infections caused by this pathogen. Understanding the mechanisms behind non-carbapenemase carbapenem resistance is critical for developing effective therapeutic strategies. This study provides crucial insights into how specific point mutations in key genes-mexR, oprD, and ftsI-contribute to carbapenem resistance, particularly the MexR (Gln55Pro) mutation’s effect on efflux pump expression and the OprD (Trp415*) truncation’s impact on porin structure. The findings elucidate the complex interplay of these mutations, highlighting their roles in conferring high-level resistance, and underscore the imperative for continued research to inform therapeutic strategies against CRPA infections.
Islam Sayah, Ibtissem Chakroun, Claudio Gervasi
et al.
Bacterial nanocellulose (BNC) has gained considerable interest over the last decade due to its unique properties and versatile applications. However, the low yield and the high production cost significantly limit its industrial scalability. The proposed study explores the isolation of new BNC producers from date palm sap and the use of date waste extract as a sustainable carbon source to improve BNC productivity. Results revealed three potential BNC producers identified as <i>Komagataeibacter</i> sp. IS20, <i>Komagataeibacter</i> sp. IS21, and <i>Komagataeibacter</i> sp. IS22 with production yield of 1.7 g/L, 0.8 g/L and 1.8 g/L, respectively, in Hestrin-Schramm (HS) medium. The biopolymer characterization indicated the presence of type I cellulose, a high thermal stability, and a highly dense network made of cellulose nanofibrils for all BNC samples. The isolate IS22, showing the highest productivity, was selected for an optimization procedure using a full factorial design with date waste extract as a carbon source. The BNC yield increased to 6.59 g/L using 4% date waste extract and 2% ethanol after 10 days of incubation compared to the standard media (1.8 g/L). Two probiotic strains, including <i>Bacillus subtilis</i> (BS), and <i>Lactobacillus plantarum</i> (LP) were successfully encapsulated into BNC matrix through a co-culture approach. The BNC-LP and BNC-BS composites showed antibacterial activity against <i>Pseudomonas aeruginosa</i>. BNC–probiotic composites have emerged as a promising strategy for the effective delivery of viable probiotics in a wide range of applications. Overall, this study supports the use of date waste extract as a sustainable carbon source to enhance BNC productivity and reduce the environmental footprint using a high-yielding producer (IS22). Furthermore, the produced BNC demonstrated promising potential as an efficient carrier matrix for probiotic delivery.
Abstract Modulating the balance between pro- and anti-inflammatory monocyte subsets holds therapeutic promise in acute myocardial infarction (AMI); however, effective and selective strategies are still lacking. In this study, we are the first to identify Ten-Eleven-Translocation 3 (TET3) expression in circulating monocytes as an independent predictor of AMI occurrence and patient prognosis in a clinical cohort. Building on this novel insight, we engineered a monocyte-targeted RNAi delivery system designed to silence TET3 expression selectively. The platform employs periodic mesoporous silica nanoparticles (PMS) loaded with siTET3, and is surface-modified with polyethylenimine (PEI) and polyethylene glycol (PEG) to enhance cellular uptake. Critically, we further functionalized the system with a CD14 receptor-recognizing transmembrane peptide (Cys-Gly-Trp-Arg-Arg-Arg-NH₂), enabling precise monocyte targeting and internalization. Our targeted nanotherapeutic successfully reprogrammed inflammatory monocytes in vitro, leading to attenuated pro-inflammatory phenotypes. In vivo, treatment with siTET3-loaded nanoparticles markedly reduced infarct size and myocardial fibrosis in murine AMI models. Importantly, translational validation in a porcine AMI model demonstrated substantial suppression of cardiac inflammation and improved post-infarction outcomes following systemic administration of the nanotherapeutic. Graphical abstract
Massive irreparable rotator cuff tears are difficult to restore when the tendon quality is poor, and the tendon retraction prevents complete repair. In such cases, tendon allograft bridging can restore continuity but cannot replicate the native tendon–bone interface. In this study, we evaluated an Achilles-tendon–bone block allograft (BTA) for anatomic tendon–bone interface reconstruction in a rabbit model of chronic massive rotator cuff tear. Thirty-six rabbits underwent bilateral infraspinatus tendon detachment, followed by repair after 3 weeks using direct suture (DS), tendon allograft without bone block (TA), or BTA. At 8 and 16 weeks, we assessed the magnetic-resonance-imaging-based tendon maturation (signal-to-noise quotient (SNQ)), micro-computed-tomography-based bone volume fraction (BV/TV) and histology, immunohistochemistry (COL I, II, X), and biomechanical-testing-based healing. The BTA group showed superior tendon continuity, significantly lower SNQ, and higher BV/TV than the DS and TA groups (p < 0.05) at both timepoints. The histological examination demonstrated denser collagen fibers, greater fibrocartilage formation, and complete bone–bone fusion in BTA. The immunohistochemical assessment revealed higher COL II and COL X expression, indicating advanced fibrocartilage maturation and mineralization. At 16 weeks, the BTA group achieved the highest ultimate load to failure (113.45 ± 14.45 N) and stiffness (19.65 ± 3.41 N/mm) values, exceeding those of the TA and DS groups (p < 0.05). These results indicate that the Achilles-tendon–bone block allograft bridge effectively reconstructs the layered tendon–bone interface, promotes osteointegration and fibrocartilage regeneration, and enhances biomechanical strength, all of which support its potential as a translational option for functional enthesis reconstruction in massive rotator cuff tear repair.
Jean-Yves Ekra, Eliakunda Michael Mafie, Henri Sonan
et al.
The resistance of trypanosomes to the doses of trypanocide administered by farmers to their animals acts as a real brake on efforts to control to combat African trypanosomiasis. Thus, in-depth knowledge of the use of these different molecules and their resistance profiles will be necessary to establish an integrated strategy to combat African trypanosomiasis. To achieve these objectives, a participatory survey among farmers and a resistance diagnosis of trypanosome strains identified in three regions of northern Côte d’Ivoire (Bagoué, Poro and Tchologo) was carried out using the PCR-RFLP technique, followed by sequencing of genes of interest. This study made it possible to identify three molecules that are commonly used by 85% (63/74) of farmers. In descending order of use, we identified Isometamidium chloride (43%), Diminazene aceturate (28%) and Homidium bromide (14%). Three species of trypanosomes, <i>Trypanosoma congolense</i>, <i>Trypanosoma. theileri</i> and <i>Trypanosoma vivax</i>, were identified in farms, and only one strain had the adenosine transporter gene (<i>Trypanosoma congolense</i>), but this strain was sensitive to the Diminazene aceturate molecule. Comparison of the sequence of this trypanosome strain showed that it is different to the Kenyan strain diagnosed as resistant to the Diminazene aceturate molecule. This study shows that a variety of trypanocides are used by farmers, and that the resistance profile of the strains to the Diminazene aceturate molecule could not be observed. However, it is important to further investigate the other molecules encountered in Côte d’Ivoire.
Geetika Kaur, Deepti Sharma, Shivantika Bisen
et al.
Abstract Vascular adhesion molecules play an important role in various immunological disorders, particularly in cancers. However, little is known regarding the role of these adhesion molecules in proliferative retinopathies. We observed that IL-33 regulates VCAM-1 expression in human retinal endothelial cells and that genetic deletion of IL-33 reduces hypoxia-induced VCAM-1 expression and retinal neovascularization in C57BL/6 mice. We found that VCAM-1 via JunB regulates IL-8 promoter activity and expression in human retinal endothelial cells. In addition, our study outlines the regulatory role of VCAM-1-JunB-IL-8 signaling on retinal endothelial cell sprouting and angiogenesis. Our RNA sequencing results show an induced expression of CXCL1 (a murine functional homolog of IL-8) in the hypoxic retina, and intravitreal injection of VCAM-1 siRNA not only decreases hypoxia-induced VCAM-1-JunB-CXCL1 signaling but also reduces OIR-induced sprouting and retinal neovascularization. These findings suggest that VCAM-1-JunB-IL-8 signaling plays a crucial role in retinal neovascularization, and its antagonism might provide an advanced treatment option for proliferative retinopathies.
Abstract The crystal structures of the pyribencarb E and Z stereoisomers were determined using single-crystal X-ray crystallography. The isomers were confirmed a single data respectively by crystal analysis, LC-UVD mass spectrometry, and NMR spectroscopy. Pyribencarb E crystallizes in triclinic P − 1 and the Z isomer in monoclinic P21/c, with the crystal structures showing comparable packing motifs. Moreover, molecular docking was carried out with cytochrome bc 1, revealing binding energies in the ranges of − 24.9 to − 17.6 and − 21.6 to − 14.7 kcal/mol for the E and Z isomers, respectively. Through a combined experimental and theoretical approach, this study contributes to our understanding of pesticides. Graphical Abstract
Abstract Type I interferon (IFN-I) plays crucial roles in the regulation of inflammation and it is associated with various inflammatory diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and periodontitis, impacting people's health and quality of life. It is well-established that IFN-Is affect immune responses and inflammatory factors by regulating some signaling. However, currently, there is no comprehensive overview of the crucial regulatory role of IFN-I in distinctive pathways as well as associated inflammatory diseases. This review aims to provide a narrative of the involvement of IFN-I in different signaling pathways, mainly mediating the related key factors with specific targets in the pathways and signaling cascades to influence the progression of inflammatory diseases. As such, we suggested that IFN-Is induce inflammatory regulation through the stimulation of certain factors in signaling pathways, which displays possible efficient treatment methods and provides a reference for the precise control of inflammatory diseases.
Carolina T. Macedo, Carolina T. Macedo, Carolina T. Macedo
et al.
AimPrevious studies showed that granulocyte-colony stimulating factor (G-CSF) improved heart function in a mice model of Chronic Chagas Cardiomyopathy (CCC). Herein, we report the interim results of the safety and efficacy of G-CSF therapy vs. placebo in adults with Chagas cardiomyopathy.MethodsPatients with CCC, New York Heart Association (NYHA) functional class II to IV and left ventricular ejection fraction (LVEF) 50% or below were included. A randomization list using blocks of 2 and 4 and an allocation rate of 1:1 was generated by R software which was stratified by functional class. Double blinding was done to both arms and assessors were masked to allocations. All patients received standard heart failure treatment for 2 months before 1:1 randomization to either the G-CSF (10 mcg/kg/day subcutaneously) or placebo group (1 mL of 0.9% saline subcutaneously). The primary endpoint was either maintenance or improvement of NYHA class from baseline to 6–12 months after treatment, and intention-to-treat analysis was used.ResultsWe screened 535 patients with CCC in Salvador, Brazil, of whom 37 were randomized. Overall, baseline characteristics were well-balanced between groups. Most patients had NYHA class II heart failure (86.4%); low mean LVEF was 32 ± 7% in the G-CSF group and 33 ± 10% in the placebo group. Frequency of primary endpoint was 78% (95% CI 0.60–0.97) vs. 66% (95% CI 0.40–0.86), p = 0.47, at 6 months and 68% (95% CI 0.43–0.87) vs. 72% (95% CI 0.46–0.90), p = 0.80, at 12 months in placebo and G-CSF groups, respectively. G-CSF treatment was safe, without any related serious adverse events. There was no difference in mortality between both arms, with five deaths (18.5%) in treatment vs. four (12.5%) in the placebo arm. Exploratory analysis demonstrated that the maximum rate of oxygen consumption during exercise (VO2 max) showed an improving trend in the G-CSF group.ConclusionG-CSF therapy was safe and well-tolerated in 12 months of follow-up. Although prevention of symptom progression could not be demonstrated in the present study, our results support further investigation of G-CSF therapy in Chagas cardiomyopathy patients.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT02154269].
Diseases of the circulatory (Cardiovascular) system
Nanxia Zhao, Nicola L. Francis, Shuang Song
et al.
Neuroinflammation is one of the hallmarks contributing to Parkinson's disease (PD) pathology, where microglial activation occurs as one of the earliest events, triggered by extracellular α‐synuclein (aSYN) binding to the cluster of differentation 36 (CD36) receptor. Herein, CD36‐binding nanoparticles (NPs) containing tartaric acid–based amphiphilic macromolecules (AMs) are rationally designed to inhibit this aSYN–CD36 binding. In silico docking reveals that four AMs with varying alkyl side chain lengths present differential levels of CD36 binding affinity and that an optimal alkyl chain length promotes the strongest inhibitory activity toward aSYN–CD36 interactions. In vitro competitive binding assays indicate that the inhibitory activity of AM‐based NPs plateaus at intermediate side chain lengths of 12 and 18 carbons, supporting the in silico docking predictions. These intermediate‐length AM NPs also has significantly stronger effects on reducing aSYN internalization and inhibiting proinflammatory molecules tumor necrosis factor α (TNF‐α) and nitric oxide from aSYN‐challenged microglia. All four NPs modulate the gene expression of aSYN‐challenged microglia, downregulating proinflammatory genes TNF, interleukin 6 (IL‐6), and IL‐1β, and upregulating anti‐inflammatory genes transforming growth factor β (TGF‐β) and Arg1 expression. Herein, overall, a novel polymeric nanotechnology platform is represented that can be used to modulate aSYN‐induced microglial activation.
New drug development is currently very expensive and time-consuming. In addition, some drugs that are approved after animal and clinical trials have their approval revoked because of adverse effects. About 30% of such drugs have heart side effects. Conventional cell-based drug toxicity tests are performed under conditions entirely different from the in vivo environment, and animal testing for drug evaluation has limitations because of differences between species. Therefore, researchers are increasingly focusing on developing models that can overcome these limitations to enable accurate drug toxicity tests. This review outlines biomimetic in vitro heart platforms, such as heart organoids, 3-dimensional bioprinting, and heart-on-a-chip devices, and describes their advantages, limitations, future perspectives. The development and use of effective cardiac biomimetic models could contribute to the development of alternatives to animal testing by providing more specific information on drug metabolism and reducing the rate of failure in later stages of drug development.
Biotechnology, Miscellaneous systems and treatments